Abused drugs produce long-lasting changes in behaviors via biochemical mechanisms that are largely unknown. Drug-altered changes in expression of specific genes in the brain can provide a major window on possible biochemical substrates for addiction. To further explore this area, we have established and developed subtracted differential display techniques that have allowed identification of more than 200 distinct cDNAs that correspond to candidate drug-regulated genes expressed in brain. During this FY, we have characterized 20 of candidate genes whose expression is regulated by amphetamine, cocaine or morphine. Sequence analyses of these cDNAs reveal that they fall into three groups: novel cDNAs, those previously described as sequences only, and those that fall into specific gene families with functional implications